EP0354412B1 - Verfahren zur Herstellung von hochreinem Ebselen - Google Patents
Verfahren zur Herstellung von hochreinem Ebselen Download PDFInfo
- Publication number
- EP0354412B1 EP0354412B1 EP89113827A EP89113827A EP0354412B1 EP 0354412 B1 EP0354412 B1 EP 0354412B1 EP 89113827 A EP89113827 A EP 89113827A EP 89113827 A EP89113827 A EP 89113827A EP 0354412 B1 EP0354412 B1 EP 0354412B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- dichloroethane
- reaction
- solution
- diselenosalicylic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 3
- 229950010033 ebselen Drugs 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 35
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 34
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 13
- 239000011669 selenium Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- APVUVAHXXOPEFF-UHFFFAOYSA-N 2-chlorobenzenecarboselenoyl chloride Chemical compound ClC(=[Se])C1=CC=CC=C1Cl APVUVAHXXOPEFF-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 10
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 claims description 10
- 229910052711 selenium Inorganic materials 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VPQBLCVGUWPDHV-UHFFFAOYSA-N sodium selenide Chemical compound [Na+].[Na+].[Se-2] VPQBLCVGUWPDHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 5
- 238000010533 azeotropic distillation Methods 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 claims description 3
- 229950011008 tetrachloroethylene Drugs 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims 2
- 239000003610 charcoal Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- MQUNPMBEKMVOHA-UHFFFAOYSA-N (sodiodiselanyl)sodium Chemical compound [Na][Se][Se][Na] MQUNPMBEKMVOHA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- XIMIGUBYDJDCKI-UHFFFAOYSA-N diselenium Chemical compound [Se]=[Se] XIMIGUBYDJDCKI-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- -1 selenium organic compound Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BHCZOKQWDQZQFK-UHFFFAOYSA-N 2-(2-carboxyphenyl)selanylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[Se]C1=CC=CC=C1C(O)=O BHCZOKQWDQZQFK-UHFFFAOYSA-N 0.000 description 1
- 241001136792 Alle Species 0.000 description 1
- 240000006108 Allium ampeloprasum Species 0.000 description 1
- 235000005254 Allium ampeloprasum Nutrition 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D293/12—Selenazoles; Hydrogenated selenazoles
Definitions
- the invention relates to a process for the preparation of high-purity Ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H) -one) of the formula I.
- Ebselen is a pharmacologically active and extremely non-toxic selenium organic compound with valuable pharmacological, eg anti-inflammatory properties (N. Dereu, E. Graf; Drugs of the Future Vol. 9, No. 10, 741 (1984)).
- Ebselen has been manufactured as follows: Selenium is in an alkaline aqueous solution with sodium formaldehyde sulfoxylate (Rongalit; trademark of BASF) according to L.Tschugaeff and W. Chlopin, Ber. 47 , 1269-1275 (1914) reduced in alkaline solution at temperatures of 70-80 ° C. and the sodium diselenide obtained crystallized out by cooling the mother liquor obtained; the sodium diselenide obtained was obtained according to A. Ruwet and M. Renson, Bull. Soc. Chim.
- the object of the present invention is to find a method by which Ebselen can be produced with high purity simply, safely and inexpensively.
- the process according to the invention is based on the known reduction of metallic selenium with the aid of sodium formaldehyde sulfoxylate (Rongalit; trademark of BASF) in aqueous alkaline solution to sodium selenide, conversion of the sodium selenide obtained with diazotized anthranilic acid in alkaline medium to the sodium salt of o-diselenosalicylic acid , Reaction of the free o-diselenosalicylic acid with excess thionyl chloride to form the o-chloroselenobenzoic acid chloride and reaction of the chloroselenobenzoic acid chloride with aniline in an organic solvent.
- the anhydrous suspension is mixed with 13 ml of ethyl 99% dimethylformamide. Under reflux temperature and vigorous stirring 5.94 kg (49.45 mol) of thionyl chloride z. Synth ⁇ 99% dropped in as quickly as possible.
- the amount of thionyl chloride must be adjusted to the dry weight of o-diselenosalicylic acid calculated above (molar ratio 1: 4.4).
- the mixture is stirred under reflux for a further 1 hour (end of gas evolution).
- the 1,2-dichloroethane is stirred distilled off (bath temperature approx. 140 o C); then it is dried in a water ring vacuum (approx. 110 mbar).
- the precipitated product is filtered off, washed twice with about 15 kg of water and sucked dry.
- the last final wash water must have a pH of 7-7.5.
- Rohebselen The moist Rohebselen is dried to constant weight in a vacuum drying cabinet at 80 o C and 15 mg Hg.
- Rohebselen Yield 4.8 kg dry weight
- Recrystallization from butanone-2 4.3 kg of dried raw lees are mixed in a reactor with 86 l of butanone-2 in a chemically pure manner and dissolved with refluxing and stirring.
- 0.43 kg of activated charcoal are added, after cooling to 70 o C and stirred for 30 minutes under reflux.
- the clear, light yellow filtrate is cooled to 20 ° C. with stirring.
- the precipitate is filtered off and dried in a vacuum drying cabinet at 60 o C and 15 mm Hg to constant weight. Yield: 3.0 kg dry weight - mp: 181 - 183 o C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3827093 | 1988-08-10 | ||
| DE3827093A DE3827093A1 (de) | 1988-08-10 | 1988-08-10 | Verfahren zur herstellung von hochreinem ebselen |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP0354412A2 EP0354412A2 (de) | 1990-02-14 |
| EP0354412A3 EP0354412A3 (en) | 1990-07-11 |
| EP0354412B1 true EP0354412B1 (de) | 1995-01-18 |
Family
ID=6360566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89113827A Expired - Lifetime EP0354412B1 (de) | 1988-08-10 | 1989-07-27 | Verfahren zur Herstellung von hochreinem Ebselen |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5008394A (fi) |
| EP (1) | EP0354412B1 (fi) |
| JP (1) | JPH0830064B2 (fi) |
| AT (1) | ATE117297T1 (fi) |
| CA (1) | CA1333175C (fi) |
| DE (2) | DE3827093A1 (fi) |
| DK (1) | DK173836B1 (fi) |
| ES (1) | ES2066811T3 (fi) |
| FI (1) | FI92694C (fi) |
| IE (1) | IE65777B1 (fi) |
| NO (1) | NO177142C (fi) |
| PT (1) | PT91414B (fi) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3937169A1 (de) * | 1989-11-08 | 1991-05-16 | Nattermann A & Cie | Benzylselenobenzamide von anilinen und benzylaminen |
| RU2143898C1 (ru) * | 1993-10-27 | 2000-01-10 | Дайити Фармасьютикал Ко., Лтд. | Гранулированный фармацевтический препарат и водная суспензия на его основе |
| DE4422237A1 (de) | 1994-06-24 | 1996-01-04 | Gruenenthal Gmbh | Verwendung von Lactamverbindungen als pharmazeutische Wirkstoffe |
| CN1166651C (zh) * | 2001-06-08 | 2004-09-15 | 北京大学药学院 | 具有抗炎和抗肿瘤作用r-双或糖苯丙异硒唑取代化合物 |
| WO2003010153A1 (en) * | 2001-07-26 | 2003-02-06 | Samsung Electronics Co. Ltd. | N-alkyl-n-phenylhydroxylamine compounds containing metal chelating groups, their preparation and their therapeutic uses |
| WO2003010143A1 (en) * | 2001-07-26 | 2003-02-06 | Samsung Electronics Co., Ltd. | Dialkylhydroxybenzoic acid derivatives containing metal chelating groups and their therapeutic uses |
| WO2003010154A1 (en) * | 2001-07-26 | 2003-02-06 | Samsung Electronics Co. Ltd. | Seleno compounds containing nitrone moiety, their preparation and their therapeutic uses |
| US7541365B2 (en) | 2001-11-21 | 2009-06-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| TWI291467B (en) | 2002-11-13 | 2007-12-21 | Millennium Pharm Inc | CCR1 antagonists and methods of use therefor |
| US20080293777A1 (en) * | 2007-05-23 | 2008-11-27 | Erlanson Daniel A | Weight Loss Treatment |
| WO2010056710A1 (en) * | 2008-11-11 | 2010-05-20 | Biovista, Inc. | Compositions and methods for treating eye diseases |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
| AU2017267732B2 (en) | 2016-05-18 | 2023-04-13 | Sound Pharmaceuticals Incorporated | Treatment of Meniere's disease |
| US20230218644A1 (en) | 2020-04-16 | 2023-07-13 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
| CN113105379A (zh) * | 2021-03-02 | 2021-07-13 | 暨南大学 | 一种以吊白块为还原剂制备硒代胱氨酸的方法及装置 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3027073C2 (de) * | 1980-07-17 | 1985-03-07 | A. Nattermann & Cie GmbH, 5000 Köln | Pharmazeutische Präparate, enthaltend 2-Phenyl-1,2-benzisoselenazol-3(2H)-on |
| DE3226286A1 (de) * | 1982-07-14 | 1984-01-19 | A. Nattermann & Cie GmbH, 5000 Köln | Cycloalkylderivate von benzisoselenazolonen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| DE3407511A1 (de) * | 1984-03-01 | 1985-09-05 | A. Nattermann & Cie GmbH, 5000 Köln | Benzisoselenazolthione, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
-
1988
- 1988-08-10 DE DE3827093A patent/DE3827093A1/de not_active Ceased
-
1989
- 1989-07-27 DE DE58908900T patent/DE58908900D1/de not_active Expired - Lifetime
- 1989-07-27 ES ES89113827T patent/ES2066811T3/es not_active Expired - Lifetime
- 1989-07-27 AT AT89113827T patent/ATE117297T1/de not_active IP Right Cessation
- 1989-07-27 EP EP89113827A patent/EP0354412B1/de not_active Expired - Lifetime
- 1989-07-28 IE IE246889A patent/IE65777B1/en not_active IP Right Cessation
- 1989-08-03 FI FI893684A patent/FI92694C/fi active IP Right Grant
- 1989-08-04 NO NO893169A patent/NO177142C/no not_active IP Right Cessation
- 1989-08-04 CA CA000607636A patent/CA1333175C/en not_active Expired - Lifetime
- 1989-08-09 JP JP1204910A patent/JPH0830064B2/ja not_active Expired - Lifetime
- 1989-08-09 PT PT91414A patent/PT91414B/pt not_active IP Right Cessation
- 1989-08-09 US US07/391,890 patent/US5008394A/en not_active Expired - Lifetime
- 1989-08-09 DK DK198903903A patent/DK173836B1/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02124880A (ja) | 1990-05-14 |
| ES2066811T3 (es) | 1995-03-16 |
| DK390389A (da) | 1990-02-11 |
| DK173836B1 (da) | 2001-12-10 |
| DK390389D0 (da) | 1989-08-09 |
| DE58908900D1 (de) | 1995-03-02 |
| FI893684A0 (fi) | 1989-08-03 |
| EP0354412A2 (de) | 1990-02-14 |
| DE3827093A1 (de) | 1990-02-15 |
| PT91414A (pt) | 1990-03-08 |
| FI893684A (fi) | 1990-02-11 |
| PT91414B (pt) | 1995-05-04 |
| IE65777B1 (en) | 1995-11-15 |
| FI92694B (fi) | 1994-09-15 |
| ATE117297T1 (de) | 1995-02-15 |
| NO893169L (no) | 1990-02-12 |
| US5008394A (en) | 1991-04-16 |
| JPH0830064B2 (ja) | 1996-03-27 |
| NO177142C (no) | 1995-07-26 |
| IE892468L (en) | 1990-02-10 |
| NO177142B (no) | 1995-04-18 |
| NO893169D0 (no) | 1989-08-04 |
| CA1333175C (en) | 1994-11-22 |
| EP0354412A3 (en) | 1990-07-11 |
| FI92694C (fi) | 1994-12-27 |
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